Neuropsychiatric SLE consists of 19 defined neuropsychiatric syndromes, of which cognitive dysfunction is one of the most disabling and least understood. Cognitive dysfunction occurs in more than 25% of SLE patients. In some patients cognitive dysfunction is due to stroke, but in others its cause is unknown. Autoantibody-induced neuronal cytotoxicity is a possible cause for cognitive dysfunction, and autoantibody to the NMDA receptor may play a role in cognitive dysfunction. We propose that cognitive dysfunction is due to both regional (by vascular occlusion) and global (by antibody to the NMDA receptor) brain injury, the latter by glutamate excitotoxicity due to the antibody.This application has the following aims: to characterize cognitive dysfunction in patients in whom lupus disease activity, damage, atherosclerosis, and antiphospholipid antibody are quantified; to determine the association of anti-NMIDA (glutamate) receptor and antiphospholipid antibodies to cognitive dysfunction, to test whether magnetic resonance spectroscopy detects lesions that underlie cognitive dysfunction, and to delineate the relationship of MRS abnormalities to anti-NMDA receptor antibody, lupus disease activity, atherosclerosis, and antiphospholipid antibody. We will do this by carefully assessing, with two independent methods, cognitive function in an already well characterized population of SLE patients who do not have MRI evidence of vascular injury, by obtaining MRS evaluations focusing on the hippocampus, by testing for anti-NMDA and antiphospholipid antibody, and by establishing correlations with measures of SLE activity, damage, and atherosclerosis. We expect to find: that distinguishable forms of cognitive dysfunction are mediated by vascular occlusion (due to atherosclerosis or antiphospholipid antibody) and by NMDA receptor antibody-induced excitotoxic response; that vascular occlusion or stroke causes cognitive dysfunction that correlates with SLE activity and damage, with antiphospholipid antibody, and atherosclerosis risk factors; and that excitotoxic neuron death correlates with anti-NMDA antibody. Successful completion of this research will redefine the pathogenesis of cognitive dysfunction and suggest therapeutic targets for intervention.